BR112020012004A2 - medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis, and, use of a medicinal composition in the field of the invention - Google Patents

Abstract

A medicinal composition for preventing or treating secondary hyperparathyroidism in maintenance dialysis, said medicinal composition comprising 3 - {[(2S) -2-amino-2-carboxyethyl] acid carbamoylamino} -5-chloro-4-methylbenzenesulfonic or a pharmaceutically acceptable salt thereof, or a solvate thereof, which must be administered by a predefined route in a predefined dosage. According to the present invention, it is possible to provide a prophylactic or therapeutic agent for secondary hyperparathyroidism in maintenance dialysis, said agent showing reduced side effects or no significant accumulation. This medicinal agent facilitates administration management and has high security compared to conventional products.

Description

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MEDICINAL COMPOSITION TO PREVENT OR TREAT SECONDARY HYPERPARATHYROIDISM IN MAINTENANCE DIALYSIS AND USE OF A MEDICINAL COMPOSITION FIELD OF THE INVENTION

[001] The present invention relates to a medicinal composition for preventing and treating secondary hyperparathyroidism in maintenance dialysis, and a method for treating it, and the like, wherein 3 - {[(2S) -2-amino acid -2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzosulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is administered with a specific dosage and administration.

TECHNICAL FUNDAMENTALS

[002] Parathyroid hormone (PTH) produced in parathyroid cells has effects on the kidneys to increase the reabsorption of calcium (Ca) and suppress the reabsorption of inorganic phosphorus (P) from urine. It also improves the production of activated vitamin D, which promotes intestinal absorption of Ca. This hormone additionally has effects on bone and promotes bone absorption, whereby Ca and P homeostasis is maintained in the body. PTH secretion is increased in response to decreased Ca, increased P and decreased vitamin D activated in the blood.

[003] In cases of chronic kidney disease, as kidney function decreases with pathological progression, P excretion in urine decreases and activated vitamin D decreases due to failure to activate vitamin D, which results in hyperphosphatemia and hypocalcemia and leads to increased PTH secretion. Persistent stimulation of PTH secretion into the parathyroid glands increases the proliferation of parathyroid cells, and parathyroid hyperplasia causes excessive PTH secretion, which results in the appearance and progression of the condition of secondary hyperparathyroidism (SHPT). In particular, SHPT is often caused in dialysis patients, where excessive PTH induces high turnover bone lesions (fibrous osteitis), increasing Ca and P in the blood. This is problematic because not only

2/33 quality of life decreases, but it also causes cardiovascular calcification, which leads to poor life prognosis (Non-patent document 1: Nobuo NAGANO, Takehisa KAWATA, Michihito WADA, Pharmacological and clinical profiles of calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients on dialysis (cinacalcet hydrochloride, REGPARA (registered trademark) tablet), Folia Pharmacologica Japonica, 2008; 132: 301-308).

[004] While conventional medical treatments to lower PTH in the blood employ the use of activated vitamin D formulations, their therapeutic effects were considered insufficient because their administration is limited to the problem of increased blood concentrations of Ca and P caused by increased blood pressure. intestinal absorption.

[005] A recently launched oral CaSR activator, cinacalcet hydrochloride (hereinafter, cinacalcet), reduces not only PTH, but also Ca and P in the blood, suppressing PTH secretion, as when the concentration of Ca2 + as an endogenous ligand is increased (Non-patent document 2: Fukagawa M et al., KRN1493 study group, Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients, Nephrol Dial Transplant. 2008; 23 (1): 328-35).

[006] Cinacalcet administration, however, is known to frequently manifest digestive symptoms, such as nausea and vomiting, and therefore has a problem with patients who need to stop administration or who cannot increase the dose (Document no. patent 3: REGPARA (registered trademark) tablet, Medicine Interview Form (pp. 1-2: 1. Development History), Kyowa Hakko Kirin (revised April 2015), and Non-patent document 4: Gincherman Y et al., Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis, Hemodial Int. 2010; 14 (1): 68-72). Although the details of the mechanism involved in the symptoms

3/33 digestive effects caused by cinacalcet are unknown, it is suggested that the increased secretion of gastric acid and the weak peristaltic movement of the digestive tract by CaSR activation in the digestive tract are some of the possible causes (Non-patent document 5: Toshiyuki DATE, Side effects of Cinacalcet and Countermeasures Thereof, Takashi AKIBA, Tadao AKIZAWA (eds.), Dialysis Treatment Next IX, Igakutosho Shuppan, Tokyo, 2009, pp. 123-32).

[007] In addition, a CaSR agonist, etelcalcetide (N-acetyl-S - [(2R) -2-amino-2-carboxyethylsulfanyl hydrochloride] -D-cysteinyl-D-alanyl-D-arginyl -D-arginyl -D-arginyl-D-alanyl-D-argininamide), was launched under the trade name PARSABIV (trademark) in 2017 as an intravenous formulation with efficacy and effect for secondary hyperparathyroidism in hemodialysis. Ethelcalcetide, however, presents problems such as excessive decrease in serum Ca concentration, accumulative properties and the like and, therefore, requires regular checking of the patient's condition and consideration of treatments such as weight reduction and medication interruption, in addition to requiring management careful use of medication due to side effects such as hypersensitivity reaction and vomiting (Non-patent document 6: PARSABIV (registered trademark), Medicine Interview Form (p. 9: V. Items Relating to Treatment, pp. 47-50: 8. Side effects), Ono Pharmaceutical Co., Ltd., Non-patent document 7: Kidney International Reports (2017) 2, 634-644, and Non-patent document 8: Clinical Nephrology, Vol. 88 No 2, 2017, 68-78).

[008] In this regard, WO2011 / 108690 (patent document 1) and JP 2013-63971 A (patent document 2) show that (2S) -2-amino-3 - {[(3-chloro- 2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic activates CaSR, while Patent Document 2 shows that oral administration of it in nephrectomized rats decreases PTH.

BACKGROUND DOCUMENTS Patent documents

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[009] Patent document 1: WO2011 / 108690 Patent document 2: JP 2013-63971 A Non-patent documents

[0010] Non-patent document 1: Folia Pharmacologica Japonica 2008; 132: 301-308 Non-patent document 2: Nephrol Dial Transplant. 2008; 23 (1): 328-35 Non-patent document 3: REGPARA (registered trademark) tablet, Medicine Interview Form (pp. 1-2: 1. Development History), Kyowa Hakko Kirin (revised in April 2015) Non-patent document 4: Hemodial Int. 2010; 14 (1): 68-72 Non-patent document 5: Toshiyuki DATE, Side effects of Cinacalcet and Countermeasures Thereof, Takashi AKIBA, Tadao AKIZAWA (eds.), Dialysis Treatment Next IX, Igakutosho Shuppan, Tokyo, 2009, pp. 123-32 Non-patent document 6: PARSABIV (registered trademark) Medicine Interview Form (p. 9: V. Items Relating to Treatment, pp. 47-50: 8. Side effects), Ono Pharmaceutical Co., Ltd.

[0011] Non-patent document 7: Kidney International Reports (2017) 2, 634-644 Non-patent document 8: Clinical Nephrology, Vol. 88 No. 2, 2017, 68-78

SUMMARY OF THE INVENTION Problem to be solved by the invention

[0012] In order to prevent or treat secondary hyperparathyroidism in maintenance dialysis, there has been a demand for a highly convenient and excellent medicinal composition. Means to Solve the Problem

[0013] In view of the problems described above, the present

5/33 inventors underwent intense investigation and, as a result, found that 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid (hereinafter, Compound A), a pharmaceutically acceptable salt of the same or a solvate of the same is effective with a specific dosage and administration in preventing or treating secondary hyperparathyroidism in maintenance dialysis, thus carrying out the present invention. [Chemical formula 1]

[0014] Specifically, the present invention comprises, for example, the aspects described below.

[0015] A medicinal composition for prevention or treatment or a method for treating secondary hyperparathyroidism on maintenance dialysis, wherein 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro- 4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and doses of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and further more preferably 0.05 to 0.2 mg.

[0016] A medicinal composition for prevention or treatment or a method for treating secondary hyperparathyroidism in dialysis of

6/33 maintenance with reduced side effects, in which 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate it is administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and doses of 2.5 mg, 0.8 mg , 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and even more preferably 0.05 to 0.2 mg.

[0017] A medicinal composition for prevention or treatment or method for treating secondary hyperparathyroidism in maintenance dialysis without manifestation of significant cumulative property, in which 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0, 05 mg or more and doses of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0, 4 mg and even more preferably 0.05 to 0.2 mg.

[0018] A medicinal composition for prevention or treatment or method for treating secondary hyperparathyroidism on maintenance dialysis for long-term administration, where 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} - 5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0 , 05 mg or more and doses of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0 , 4 mg and even more preferably 0.05 to 0.2 mg.

[0019] The medicinal composition or the therapeutic method according

7/33 with any of the above, where the end of dialysis means the end of each dialysis session in a dialysis plan of 3 to 5 sessions per week.

[0020] The medicinal composition or therapeutic method according to any of the above aspects, wherein 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulphonic acid , a pharmaceutically acceptable salt thereof or a solvate thereof is 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate or a solvate thereof.

[0021] The medicinal composition or therapeutic method according to any of the above, wherein 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulphonic acid , a pharmaceutically acceptable salt thereof or a solvate thereof is sodium 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate.

[0022] In particular, the following are preferred aspects.

[0023] [1] A medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis, the composition comprising 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4 acid -methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults.

[0024] [2] A medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis with reduced side effects, the composition comprising 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5- chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults.

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[0025] [3] A medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis without manifesting significant cumulative property, the composition comprising 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino acid} -5-chloro-4-methyl-benzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults.

[0026] [4] The medicinal composition according to any one of [1] to [3], which is administered intravenously with a daily dose of 0.025 to 0.4 mg for adults.

[0027] [5] The medicinal composition according to any one of [1] to [3], which is administered intravenously at the end of dialysis with a daily dose of 0.05 to 0.2 mg for adults.

[0028] [6] The medicinal composition according to any of [1] to [5], where the end of dialysis means the end of each dialysis session on a dialysis schedule of 3 to 5 sessions per week.

[0029] [7] The medicinal composition according to any one of [1] to [6], wherein 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro- 4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is sodium 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate or a solvate thereof.

[0030] Another aspect of the present invention comprises a medicinal composition for prevention or treatment or a method for treating secondary hyperparathyroidism in maintenance dialysis, wherein the composition comprises Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof and the composition is administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and doses

9/33 of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and further more preferably 0.05 to 0.2 mg to regulate the serum PTH concentration to the normal level.

[0031] In addition, another aspect of the present invention comprises a medicinal composition to prevent or treat or a method for treating secondary hyperparathyroidism in maintenance dialysis, wherein Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, and the composition is administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and doses of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and even more preferably 0.05 to 0.2 mg to regulate the concentration of serum PTH and Ca at normal levels.

[0032] Alternatively, another aspect of the present invention comprises a medicinal composition or a method for regulating the concentration of serum PTH in a patient with secondary hyperparathyroidism on normal maintenance dialysis, wherein the composition comprises Compound A, a pharmaceutically salt acceptable dose or a solvate of the same, and the composition is administered intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and doses 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and even more preferably 0 , 05 to 0.2 mg. The aspect further comprises a medicinal composition or a method for regulating serum PTH and Ca concentrations in a patient with secondary hyperparathyroidism on normal maintenance dialysis, wherein the composition comprises Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, and the composition is administered

10/33 intravenously at the end of dialysis with a daily dose for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and from doses of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less, preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and even more preferably 0.05 to 0.2 mg.

[0033] The present invention also relates to a kit comprising Compound A, a pharmaceutically acceptable salt of it or a solvate of it and a label and / or an attached instruction that instructs a daily dose for intravenous administration in adults at the end dialysis (e.g., a dose of 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and even more preferably 0.05 to 0.2 mg) to prevent or treat secondary hyperparathyroidism in maintenance dialysis.

[0034] The kit may further comprise a container for containing Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof (for example, a vial, an ampoule) and / or a box (package) for packaging said container .

[0035] In the kit described above, Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof may be a medicinal composition containing Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof and a pharmaceutically acceptable carrier ( for example, sodium chloride, disodium hydrogen phosphate or a hydrate thereof, sodium dihydrogen phosphate or a hydrate thereof).

EFFECT OF THE INVENTION

[0036] The present invention can provide an agent to prevent or treat secondary hyperparathyroidism in maintenance dialysis with reduced side effects or without manifesting significant cumulative property, which facilitates dosage management by medical practitioners and is a safer drug than conventional products and,

11/33 therefore, it is beneficial for patients and medical practitioners.

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] [Figure 1] A graph showing the relationship between the serum iPTH concentration and the doses given 48 hours after a single intravenous administration in bilaterally nephrectomized rats in Example 2.

[0038] [Figure 2] A graph showing the relationship between serum Ca concentration and doses given 48 hours after a single intravenous administration to bilaterally nephrectomized rats in Example 2.

[0039] [Figure 3] A graph comparing survival 48 hours after a single intravenous administration in bilaterally nephrectomized rats in Example 2.

[0040] [Figure 4] A graph showing the rate of histamine release from peritoneal mast cells upon administration of the respective compounds in Example 4.

[0041] [Figure 5] A graph obtained by simultaneously adjusting the changes in plasma concentrations of the three doses given in P1, using a three-compartment model.

[0042] [Figure 6] A schematic view showing an indirect response model incorporating rebound.

[0043] [Figure 7] A graph of PK / PD analysis based on P1 using the indirect response model incorporating rebound.

[0044] [Figure 8] A graph showing expected PK and the deducted EC50 value (> 1.4 ng / ml) in dialysis patients.

MODE FOR CARRYING OUT THE INVENTION

[0045] In the following, the present invention will be described in more detail. The medicinal composition of the present invention can be used for a patient who develops or is at risk of developing secondary hyperparathyroidism, specifically, a patient with a chronic kidney disease who is continuously receiving dialysis.

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[0046] "Secondary hyperparathyroidism" refers to hyperparathyroidism that occurs by the continuous presence of a factor that stimulates the parathyroid glands, which is induced by abnormal bone mineral metabolism resulting from disorders of renal function and refers to a state in which serum PTH concentration before administration of the medicinal composition of the present invention is exceeding a certain range. A PTH concentration can be measured by several measurement methods, for example, as intact PTH (iPTH) that can be acquired by measuring only full-length PTH or as whole PTH that can be acquired by measuring only biologically active full-length PTH . Based on the reference values of dialysis patients that are defined for the respective measurements, secondary hyperparathyroidism is diagnosed when the measured PTH values exceed a certain range. In general, secondary hyperparathyroidism is diagnosed in terms of the iPTH value, specifically when the iPTH exceeds 300 pg / ml and, in some cases, when the iPTH exceeds 240 pg / ml.

[0047] Here, in a case of hypoalbuminemia (albumin is 4 g / dl or less), a serum Ca concentration can be corrected by the following equation. Corrected serum Ca level [mg / dl] = Measured serum Ca level [mg / dl] + 4 - Serum albumin level [g / dl]

[0048] "Prevention" of secondary hyperparathyroidism means administering the medicinal composition of the present invention to a patient whose serum PTH concentration is within the reference range of dialysis patients prior to administration of the medicinal composition of the present invention, but who is at risk to develop secondary hyperparathyroidism due to disorders of renal function, so that the serum PTH concentration does not exceed the upper limit of the reference value for dialysis patients.

[0049] “Treatment” of secondary hyperparathyroidism means

13/33 administering the medicinal composition of the present invention to a patient developing secondary hyperparathyroidism, in order to decrease the concentration of serum PTH to a lower level than the concentration before administration of the medicinal composition of the present invention, preferably to the reference value for dialysis patients. More preferably, this means decreasing the serum PTH concentration, but not falling below the lower limit value of the reference value for patients on dialysis and not exceeding the upper limit value of said reference value. In addition, while decreasing the serum PTH concentration to the reference value for dialysis patients, this may also mean suppressing the progression of parathyroid hyperplasia and mineral metabolism disorders (especially Ca and P), which are related symptoms secondary hyperparathyroidism, preferably to improve symptoms as they were before the administration of the medicinal composition of the present invention, or to maintain parameters related to the disturbance of mineral metabolism within the reference values for dialysis patients.

[0050] "One daily dose" of Compound A "for adults selected from doses of 0.01 mg, 0.025 mg, 0.05 mg or more and from doses of 2.5 mg, 0.8 mg, 0.4 mg, 0.3 mg, 0.2 mg or less ”refers to any dose in a range of 0.01 mg to 2.5 mg, 0.01 mg to 0.8 mg, 0.01 mg to 0.4 mg, 0.01 mg to 0.3 mg, 0.01 mg to 0.2 mg, 0.025 mg to 2.5 mg, 0.025 mg to 0.8 mg, 0.025 mg to 0.4 mg , 0.025 mg to 0.3 mg, 0.025 mg to 0.2 mg, 0.05 mg to 2.5 mg, 0.05 mg to 0.8 mg, 0.05 mg to 0.4 mg, 0.05 mg to 0.3 mg or 0.05 mg to 0.2 mg. If Compound A is a solvate, the dose refers to an amount of Compound A in terms of a non-solvate. If Compound A is a solvate of a salt, the dose refers to an amount of free compound A in terms of a non-solvate. If the patient is Japanese, the dose is preferably 0.025 mg to 0.8 mg, more preferably 0.025 to 0.4 mg and even more preferably 0.05 to 0.2 mg. The preferred dose given may vary between races. For example, Caucasians,

14/33 Australoids and negroidids generally require a higher dose than the preferred dose for Mongoloids, such as the Japanese.

[0051] As the medicinal composition of the present invention is administered at the time of dialysis (through dialysis), if the general dialysis schedule consists of three sessions per week, the medicinal composition of the present invention is administered through each dialysis session. In this case, assuming that the beginning of a week is Day 1, dialysis is performed, for example, on days 1, 3 and 5, through which the medicinal composition of the present invention is administered, and the same schedule is repeated at from next week and so on. If the dialysis schedule consists of 4 sessions per week, or if more than 4 sessions are temporarily held due to the patient's condition or similar, the medicinal composition of the present invention is administered following the same schedule of 4 or more dialysis sessions per week . Preferably, the medicinal composition of the present invention is administered at the end of each dialysis session in the dialysis schedule of 3 to 5 sessions per week.

[0052] The phrase "end of dialysis" means just before the end of dialysis, specifically, when blood is returned immediately before the end of dialysis.

[0053] The phrase "administered intravenously" means to administer the drug directly into the vein, but for patients on dialysis, it is preferable to administer the drug from the venous side of the dialysis circuit.

[0054] More preferably, the drug is infused into the venous side of the dialysis circuit by returning blood at the end of the dialysis.

[0055] The term "side effects" refers to side effects that were a problem with an existing drug with the same indications, specifically digestive symptoms such as nausea and vomiting, hypersensitivity reaction, dysgeusia, hypocalcemia, exacerbation of heart failure caused by hypocalcemia, prolongation of the QT interval,

15/33 numbness, muscle spasm, feeling sick, arrhythmia, hypotension and spasm.

[0056] The term "reduced side effects" means that the occurrence of side effects caused by an existing drug with the same indications is less than said existing drug when the administration is carried out with a specific dosage and administration according to the present invention. Specifically, this means that the occurrence of said side effects is 20% or less, 15% or less, 10% or less, 5% or less, and preferably 1% or less in a patient receiving the medicinal composition of the present invention .

[0057] The phrase "without expressing significant cumulative property" means that, even if the medicinal composition of the present invention is administered continuously (for 1 month or more) with a defined dosage and administration, the concentration of Compound A in the blood does not increase significantly in proportion to the administration period.

[0058] The phrase "used for long-term administration" means that it is a medicinal composition with fewer cases of drug discontinuation, which is more adaptable to long-term administration compared to an existing drug with the same indications (cinacalcete, etelcalcetida ). Specifically, it refers to the continuous administration of 1 year or more.

[0059] The phrase "regulate to normal level" means to regulate the concentration of serum PTH or Ca to a level considered clinically not problematic by the doctor, preferably within the range of reference values for dialysis patients defined for the respective inspection values. More preferably, this means that regulation at the aforementioned level is carried out by administration within a defined range of dosage and administration, without any interruption of the medication during the administration period.

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[0060] In general, the serum iPTH concentration is in the range of 60 pg / ml to 300 pg / ml, preferably in the range of 150 pg / ml to 300 pg / ml or 60 pg / ml to 240 pg / ml.

[0061] The reference serum Ca concentration of dialysis patients (corrected serum Ca concentration in the case of hypoalbuminemia) is generally in the range of 8.4 mg / dl to 10.0 mg / dl.

[0062] Note that the normal level also includes cases in which there is no need to interrupt administration, even if the concentration may temporarily deviate from the aforementioned reference range.

The present invention comprises a medicinal composition containing Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient and a pharmaceutically acceptable carrier, such as a non-toxic pharmaceutically acceptable carrier, and also comprises a medicament which it consists only of Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0064] Compound A used for the present invention also comprises compound A in the form of a salt. If Compound A, an active ingredient of the present invention, is in the form of a salt, the salt is a pharmaceutically acceptable salt or an edible salt. Examples of salts of an acid group, such as the carboxyl group in the formula, include an ammonium salt, a salt with a metal such as sodium, potassium, calcium, magnesium, aluminum or zinc, a salt with an organic amine, such as triethylamine, ethanolamine , morpholine, pyrrolidine, piperidine, piperazine or dicyclohexylamine and a salt with a basic amino acid, such as arginine or lysine. Examples of salts of a basic group include a salt with an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or hydrobromic acid, a salt with an organic carboxylic acid, such as acetic acid, trifluoroacetic acid, citric acid, benzoic, maleic acid, fumaric acid, tartaric acid,

17/33 succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, theological acid, salicylic acid, lactic acid, oxalic acid, mandelic acid or malic acid, and a salt with an organic sulfonic acid , such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. These salts can be produced by placing said compound in contact with an acid or a base that can be used to produce a pharmaceutical product.

[0065] Preferably, it is the sodium salt of Compound A.

[0066] According to the present invention, Compound A or a salt thereof can be an anhydride and can form a solvate such as a hydrate or an alcohol adduct. As used herein, "solvation" refers to a phenomenon in which molecules or solute ions strongly attract the surrounding solvent molecules and form a single molecular cluster in a solution. For example, it is called hydration if the solvent is water. The solvate can be a hydrate or a non-hydrate. A non-hydrate can use an alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide or the like.

[0067] Preferably, it is a sodium salt hydrate of Compound A.

[0068] If Compound A is obtained in the free form, it can be converted into the form of a salt, a hydrate of the same or a solvate of the same that can result from said compound, according to a conventional procedure.

[0069] Furthermore, if Compound A is obtained as a salt, hydrate or solvate of said compound, it can be converted to a free form of Compound A, according to a conventional procedure.

[0070] Compound A is administered intravenously as a medicinal composition containing compound A as an active ingredient. The method for applying such a medicinal composition is not particularly limited and

18/33 the composition can be administered in the form of a commonly used medicinal formulation by mixing the active ingredient with a pharmaceutically acceptable non-toxic liquid carrier that is suitable for administration as an injection.

[0071] Examples of such a formulation include forms of liquid agents, such as a solution, a suspension and an emulsion, and forms such as a lyophilized agent. These formulations can be prepared by a pharmaceutically common process.

[0072] Examples of the non-toxic pharmaceutically acceptable carrier include water and physiological saline. In addition, if necessary, a common additive, such as a pH control agent, a stabilizer, an emulsifier or a tonicity agent, can also be suitably added.

[0073] The medicinal composition of the present invention can be formulated by a conventional procedure. According to the pharmaceutical need, several pharmacologically acceptable substances for formulation can be added (as adjuvants or the like). The formulation substance can be appropriately selected according to the formulation dosage form. For example, if the formulation is a solution, examples of the formulation substance include sterile water and a monohydric or polyhydric alcohol, such as glycerol.

[0074] The medicinal composition of the present invention may include a package insert instructing its use within the package. An example of such a package insert includes so-called instructions that explain the use, effectiveness, method of administration and the like.

[0075] According to the patient's symptoms, the medicinal composition of the present invention can be used in combination with a calcium agent or a vitamin D formulation. The dosage and administration of the calcium agent or vitamin D formulation used in combination

19/33 can be properly determined according to the concentration of Ca in the blood.

EXAMPLES

[0076] In the following, the present invention will be described specifically by way of examples, although the present invention should not be construed as limited to those examples. Example 1: Synthesis of 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate (Compound A1) (Step 1) Synthesis of acid 3 - ({[( 2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic

[0077] For 5 g (22.56 mmol) of 3-amino-5-chloro-4-methylbenzenesulfonic acid (ACTS), 37.5 mL (7.5 L / kg vs ACTS) of acetonitrile, 3.81 mL (47.38 mmol, 2.1 eq.) Of pyridine was added and stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO2Ph was poured into the resultant, which was stirred for 30 minutes and then the end of the carbamate reaction was confirmed by HPLC. 5.92 g (23.23 mmol, 1.03 eq.) Of 3-amino-N- (tert-butoxic arbonyl) -L-alanine methyl ester hydrochloride were added and 9.75 mL (69.93 mmol , 3.1 eq.) Of triethylamine were added to the resultant, which was stirred at 25ºC for 3 hours. 0.4 g (1.58 mmol, 0.07 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 0.22 mL (1.58 mmol, 0, 07 eq.) Of triethylamine were added and the end of the urea formation reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of methanesulfonic acid was added, and the resultant was heated to 50 ° C and stirred for 4 hours. After confirmation of the end of the deprotection by HPLC, the resultant was cooled to 25ºC and added with 37.5 mL (7.5 L / kg) of acetonitrile and 7.5 mL (1.5 L / g) of water to allow the deposition of a solid. The resultant was cooled to 5ºC and matured for 16 hours. The deposited solid was filtered under

20/33 reduced pressure, washed with 20 mL (4.0 L / kg) of water / acetonitrile (1/2) and then dried under reduced pressure at 40 ° C for 5 hours to give 7.72 g of the compound of interest as a white solid (liquid 7.20 g, 87.3%). 1

[0078] H-NMR (400 MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2 Hz), 7.90 (d, 1H, J = 1.6 Hz), 7.28 (d, 1H, J = 1.6 Hz), 6.78 (t, 1H, J = 5.6 Hz), 4.20-4.10 (m, 1H ), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H), 2.21 (s, 3H)

[0079] HRMS (FAB-): calculated for m / z 364.0369 (MH), found m / z 364.0395 (MH) (Step 2) (2) Synthesis of 3 - {[(2S) -2- amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-sodium methylbenzenesulfonate

[0080] For 10.64 g (liquid 10.0 g, 27.34 mmol) of the compound obtained in Step 1, 18 ml (1.8 L / kg vs compound from Step 1) of water were added and the resultant was stirred at 8ºC. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was poured into the resultant, which was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8ºC for 15 minutes. After confirmation of the end of the hydrolysis by HPLC, the resultant was heated to 25ºC, to which about 3.55 ml of 48% aq HBr were added to control the pH to 5.8. 65 mL (6.5 L / kg) of isopropyl alcohol was poured into the resultant. After confirming the deposition of the compound of interest, the resultant was aged for one hour. 81 mL (8.1 L / kg) of isopropyl alcohol was poured into the resultant and aged at 8ºC overnight. The deposited solid was filtered under reduced pressure, washed with 20 ml (2.0 L / kg) of isopropyl alcohol and then dried under reduced pressure at 40 ° C for 4 hours to give 10.7 g of the compound of interest as a white solid ( liquid 9.46 g, 92.6%). 1

[0081] H-NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 7.91 (d, 1H, J = 1.6 Hz), 8.00-7.50 (bs , 2H), 7.24 (d, 1H, J = 1.6 Hz), 7.20 (t, 1H, J = 5.6 Hz),

21/33 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H) Example 2: Effect of Compound A1 on serum Ca concentration and serum iPTH concentration in bilaterally nephrectomized rats

[0082] After periods of quarantine and acclimatization of 6 days, fifty-one 7-week-old rats (Crl: CD (SD), male) were fed a diet of 100% sucrose at will four days before surgery. On the day of surgery, skin incisions were made on the back of the right and left kidney sites under isoflurane anesthesia and the renal capsules were removed to connect the renal arteries and veins and the ureters using wires before removing the right and left kidneys. A penicillin solution was given by suturing and 5 mL of physiological saline was administered intraperitoneally before returning the rats to the breeding cages.

[0083] On the day of test substance administration, that is, one day after bilateral nephrectomy, approximately 100 µL of blood was collected from the tail vein without anesthesia using a capillary tube, which was centrifuged in a refrigerated high speed microcentrifuge. (10,000 rpm, 5 min, 4 ° C) to separate the serum. Subsequently, the serum Ca concentration was measured with a dri-chem analyzer (model number: FUJI DRI-CHEM 7000, manufacturer: FUJIFILM Medical Co. Ltd.) to select individuals with a serum Ca concentration of 8.0 mg / dL or more and less than 14.0 mg / dL.

[0084] The day after bilateral nephrectomy, the indicated doses were calculated based on the weight of the animals selected on that day. Group 1 received a medium (saline), groups 2, 3 and 4 received the solution of Compound A1 (0.3, 3 and 30 mg / mL, respectively) and groups 5, 6, 7 and 8 (5 rats per group) received the comparative compound (0.3, 1, 3 and 10 mg / ml, respectively), each with a single dose of 1 ml / kg of the tail vein. Before administration (0 hours) and 24 and 48 hours after administration, approximately 300 µL of blood was collected without anesthesia from the

22/33 tail, using capillary tubes to obtain the serum. The blood to obtain the serum was left to stand at room temperature and centrifuged in a refrigerated high speed microcentrifuge (10,000 rpm, 5 min, 4ºC) within a period of 30 minutes to 2 hours after collecting blood to collect the blood. serum.

[0085] Subsequently, serum Ca was analyzed with the COBAS analyzer (model number: COBAS INTEGRA 400 plus, manufacturer: Roche Diagnostics KK) and the remaining serum was stored in an ultra-low freezer (temperature adjusted to -80 ± 15ºC) until the day of the iPTH measurement. On the day of the iPTH measurement, the serum was melted at room temperature for measurement. (Compound A1 Solutions)

[0086] A 30 mg / ml solution of Compound A1 (338 mg of Compound A1 dissolved in 10 ml of physiological saline) was diluted with physiological saline to prepare 0.3 mg / ml and 1 mg / ml of saline solutions. A1. (Comparative compound solutions)

[0087] 149 mg of TFA salt of etelcalcetide (Ac-c (C) arr-NH2) (WO 2011014707) were prepared to have a pH of 6-8 with 7 ml of physiological saline and an aqueous solution of NaOH 0.5N, to which the saline solution was also added to make up 10 ml. The 10 mg / ml comparative compound solution prepared was diluted with physiological saline to give comparative 0.3 mg / ml and 1 mg / ml compound solutions. (Results) (1) Serum iPTH concentration in bilaterally nephrectomized rats

[0088] The mean ± standard error of serum iPTH concentrations in all subjects before administration (0 hour) was 231 ± 16 pg / ml. Compound A1 administrations at 0.3, 3 and 30 mg / kg decreased serum iPTH concentrations, where averages were 140, 138 and 118 mg / dL 24 hours after administration, respectively, and 338, 280 and 245 mg / dL 48 hours

23/33 after administration, respectively. Here, the plasma concentration of Compound A1 48 hours after a single intravenous dose of Compound A1 at 30 mg / kg in bilaterally nephrectomized rats was estimated at 18.8 µg / ml, maintaining a concentration sufficiently higher than the effective concentration at 50%, ie that is, an EC50 value of 75 ng / ml to decrease the serum iPTH concentration.

[0089] Meanwhile, administrations of the comparative compound at 0.3, 1, 3 and 10 mg / kg also decreased the serum iPTH concentration, where the mean serum iPTH concentrations were 122, 52, 22 and 104 mg / dL 24 hours after administration, respectively, and 510, 280, 41 and 230 (n = 1) mg / dL 48 hours after administration, respectively. Here, the concentration of the comparative compound in plasma 48 hours after a single intravenous dose of the comparative compound at 3 mg / kg in bilaterally nephrectomized rats was estimated at 0.13 µg / ml, maintaining a concentration sufficiently greater than the effective concentration at 50% , that is, an EC50 value of 40 ng / ml to decrease the serum iPTH concentration. The adjustment of the logistic curve was performed to establish the response relationship between the serum iPTH concentration 48 hours after administration and the administered dose. As a result, the lower limit values of serum iPTH concentrations by Compound A1 administrations and the comparative compound were simulated to be 203.0 pg / ml and 48.18 pg / ml, respectively (Figure 1). (2) Serum Ca concentration in bilaterally nephrectomized rats

[0090] The mean ± standard error of serum Ca concentrations of all subjects before administration (0 hour) was 11.25 ± 0.28 mg / dL.

[0091] Compound A1 administrations at 0.3, 3 and 30 mg / kg decreased serum Ca concentrations, where averages were 9.07, 7.97 and 7.99 mg / dL 24 hours after administration, respectively, and 10.24, 8.55 and 8.14 mg / dL 48 hours after administration, respectively.

[0092] Meanwhile, administrations of the comparative compound to

24/33 0.3, 1, 3 and 10 mg / kg also decreased the serum Ca concentration, where the average serum Ca concentrations were 8.33, 6.42, 6.82 and 6.95 mg / dL 24 hours after administration, respectively, and 10.44, 7.33, 5.85 and 6.65 (n = 1) mg / dL 48 hours after administration, respectively.

[0093] The adjustment of the logistic curve was performed to establish the response relationship between the serum Ca concentration 48 hours after administration and the administered dose. As a result, the lower limit values for serum Ca concentrations by the administrations of Compound A1 and the comparative compound were simulated to be 8.072 mg / dL and 5.880 mg / dL, respectively (Figure 2). (3) Survival of bilateral nephrectomized rats after single doses of Compound A1 and comparative compound

[0094] The number of rats in each group was five before administration. While all five rats survived 48 hours after administration in the group that received the medium and in the groups that received compound A1, four survived in the 3 mg / kg group and one survived in the 10 mg / kg group among the groups that received comparative compounds (Figure 3).

[0095] Compound A1 is a CaSR activator used for intravenous administration. Non-clinical studies show that renal excretion is the main route of excretion and, when the compound is administered intravenously to a normal rat, the compound is rapidly cleared from the plasma. In rat models with renal failure, serum iPTH and Ca concentrations decreased sufficiently during the 48 hours after administration, but the decreases were gradual in relation to the dose increase.

[0096] On the other hand, the etelcalcetide already launched having the same mechanism of action decreased the concentrations of serum iPTH and Ca in a dose-dependent manner, but the number of dead rats increased in a dose-dependent manner.

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[0097] These results show that Compound A1, in comparison with etelcalcetide, had an advantageous effect of not decreasing serum iPTH and Ca concentrations, affecting the maintenance of life, and that it was useful to control iPTH and Ca concentrations serum levels in patients with nephropathy. Example 3: Emetogenicity studies of Compound A1 in dogs

[0098] A crossover test was carried out with male beagles (Beagle Nosan, 14-87 months old, weight: 10.2 kg-15.8 kg). The solutions of compound A1 used in Example 2 were administered at 0.3, 1 and 10 mg / kg by bolus administration (0.5 ml / kg, 1 ml / s) to 3-6 dogs per dose to confirm the manifestation vomiting immediately after administration. Administration was performed once or twice a week, with an interval of 2 days. Administration was performed before feeding.

[0099] Symptoms were observed before, immediately after, and 15 and 30 minutes after administration. (Results)

[00100] The results are shown in Table 1. [Table 1] Table 1: State of vomiting Route of administration Dose Number of cases of vomiting / Number of (mg / kg) administration 0.3 0/3 Compound A1 Intravenous 1 0 / 3 10 1/6

[00101] For administration at 1 mg / kg without any case of vomiting in dogs, C0 was 18.8 µM. Assuming an effective dose in humans was 0.1 mg / man, in view of Example 5 below, C0 was 0.0436 µM based on the analysis results acquired while simultaneously adjusting all doses.

[00102] From the results above, it was found that Compound A1 has a therapeutic margin 430 times, or more, greater in humans than in dogs in relation to vomiting.

[00103] It is known that cinacalcet frequently manifests digestive symptoms such as nausea and vomiting, which are factors that inhibit the administration

26/33 continuous. On the other hand, as the dose of Compound A1 of the present invention administered to humans differs greatly from the dose that manifests vomiting in dogs, it appears to be a medicinal composition that has few side effects, such as vomiting in humans, that is safe and that is adaptable long-term administration. Example 4: Histamine release test using rat peritoneal mast cells

[00104] Male SD rats (10 weeks old) were used to isolate peritoneal mast cells from rats according to the method of Kimura et al. (Kimura T., Eur J Pharmacol. 2000 Nov 3; 407 (3): 327-32). Compound A1 was added to these mast cells to determine the amount of histamine released according to the method of Liu J et al. (Liu J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Nov 15; 971: 35-42) to compare the effects of Compound A1, the comparative compound, and Compound 48/80 as a positive control in histamine release. Specifically, the test substance was added to the suspension of peritoneal cells obtained from SD rats (cell concentration of 0.4 x 105 cells / ml) and the concentration of histamine in the cell supernatant was determined after incubated at 37ºC for 30 minutes. Here, etelcalcetide was used as the comparative compound; compound A1 and the comparative compound were each prepared in five groups of 0.1 µM-1000 µM in the same manner as in Example 2; and compound 48/80 (manufactured by Sigma) was tested at concentrations of 0.1 mg / ml and 10.0 mg / ml.

[00105] The inhibition ratio was calculated by the following equation. Inhibition ratio (%) = (individual group histamine concentration (µM) - negative control group histamine concentration (µM)) x 100 / (total histamine concentration (µM) - negative control group histamine concentration (µM)) (µM)) (Results)

27/33

[00106] As can be seen in Figure 4, Compound A1 has been shown to induce almost no histamine release. Meanwhile, the comparative compound increased the level of histamine released in a dose-dependent manner.

[00107] It is known that etelcalcetide has the risk of developing a hypersensitivity reaction and, therefore, requires great caution upon administration. On the other hand, since Compound A1 of the present invention is unlikely to cause histamine release, which is a major cause of the hypersensitivity reaction, it has a low probability of developing a hypersensitivity reaction and therefore has been confirmed to be a composition medicinal product with reduced side effects. Example 5: Phase I clinical trial and determination of the clinically effective amount (1) Phase I clinical trial (P1)

[00108] Thirty-two healthy male Japanese adults received a single intravenous dose of the test drug (Compound A1) of 0.01 mg, 0.1 mg, 1.0 mg or 2.5 mg fasting to study pharmacokinetics, pharmacodynamics and safety in a double-blind test using a placebo as a control. Here, the test drug was administered by diluting a required dose taken from the Compound A1 vial formulation prepared as follows with sterile water for injection and filling a syringe with the resultant according to the dose to be administered. (Compound A1 bottle formulation)

[00109] A bottle formulation that encapsulates 100 mg of Compound A1 in terms of dehydrate and sodium chloride, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate as additives in 10 ml sterile water for injection (Placebo)

[00110] A bottle formulation that encapsulates 10 ml of water

28/33 sterile for injection without Compound A1. (Results)

[00111] In the phase I trial, which targeted healthy male adults and used a placebo as a control, single intravenous doses of 0.01 mg, 0.1 mg, 1.0 mg and 2.5 mg of Compound A1 was present as substances generally unchanged in the plasma and rapidly eliminated. In addition, since they were excreted in the urine primarily as substances that were unchanged from the dose administered, renal excretion was considered the main route of elimination of the unchanged substance. In pharmacodynamic assessments, it was confirmed that the serum iPTH concentration decreased in the dose groups of 0.01 mg and higher compared to that before administration, where the duration of the decreased serum iPTH concentration extended with increasing the specified dose . As for safety, mild and non-serious side effects, such as vomiting, were observed in the 1.0 mg and higher dose groups, but no other problematic events were observed. (2) Determination of the clinically effective amount

[00112] A PK / PD analysis was performed to estimate the clinically effective dose based on the results of P1. The 2.5 mg dose seemed excessive and was therefore eliminated from the analysis. Data on PK (mean plasma concentration) and SD (mean level of iPTH normalized by the levels of the placebo group and level at zero hour) were used at doses of 0.01 mg, 0.1 mg and 1 mg. An indirect response model incorporating rebound was used for the PK / PD analysis.

[00113] Based on the PK results of the three doses given (0.01 mg, 0.1 mg and 1 mg) in P1, the three doses given were analyzed simultaneously using a three compartment model to calculate the PK parameters ( Figure 5 and Table 2). [Table 2]

29/33 Table 2: PK parameters obtained by simultaneously adjusting the changes in plasma concentrations of the three doses indicated in P1 using a three-compartment model PK parameter (± standard error) Vd (mL / kg) 90.9 ± 11.4 Ke (hr-1) 1.28 ± 0.15 K12 (hr-1) 0.658 ± 0.136 K21 (hr-1) 0.819 ± 0.049 K13 (hr-1) 4.42 ± 1.80 K31 (hr-1) 6.89 ± 1.33

[00114] Using the PK parameters calculated as an input function, the PK / PD analysis was performed using an indirect response model incorporating rebound (Figure 6) to calculate the EC50 value in healthy adults (Figure 7 and Table 3). [Table 3] Table 3: PD parameters by PK / PD analysis of P1 using indirect response model incorporating rebound PD parameter (± standard error) EC50 (ng / mL) 0.421 ± 0.167 Emax (ratio) 0.920 ± 0.027

[00115] The EC50 value in patients with renal failure was estimated based on the calculated EC50 value in healthy adults and the results of the same analysis in normal rats and adenine-treated rat models (pathological rat models). First, EC50 values were calculated in the same way in rats, which were <22.9 ng / mL in normal rats and 74.8 ng / mL in rat models treated with adenine. Since the difference in the EC50 value between normal and pathological rats is assumed to be caused by changes in PK that vary considerably between normal and pathological status, a similar trend in humans is also expected. Consequently, the scale factor of the EC50 values of healthy individuals and patients with renal failure was defined as "> 3.3". This scale factor was applied to humans, where the EC50 value was estimated as> 1.4 ng / ml in patients with renal failure.

30/33

[00116] The result of the PK adjustment and the contribution rate of renal elimination of the drug (3.2%) calculated using PK-sim (trademark) were used to simulate the PK prediction in patients with renal failure. This simulation for PK prediction and the previously estimated EC50 value in patients with renal failure (> 1.4 ng / mL) were used to estimate a given dose that allows the plasma drug concentration to maintain the EC50 value for 72 hours in patients with renal failure, which was assumed to be the estimated clinically effective dose. As a result, it is estimated that the administration of a dose of 0.06 mg / man maintains a concentration greater than 1.4 ng / ml for 72 hours (Figure 8). The clinically effective dose was estimated as 0.1 mg / man, considering that its EC50 value exceeds 1.4 ng / ml. Example 6: Phase I / II clinical trials

[00117] SHPT patients undergoing maintenance hemodialysis, pharmacokinetics, pharmacodynamics and safety through single or repeated intravenous administration of Compound A1 were examined by performing a double-blind test using a placebo as a control.

[00118] Single administration: Based on the clinically effective dose calculated in Example 5, doses were administered at 0.025 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg and 0.8 mg (7 steps). On the day of the test drug administration, the test drug was administered intravenously as slowly as possible within 60 seconds, 2 to 4 hours after the end of dialysis. Here, the test drug was administered by diluting a required dose taken from the Compound A1 bottle formulation prepared as follows with sterile water for injection and filling a syringe with the resultant according to the dose to be administered.

[00119] Repeated administration: Based on the clinically effective dose calculated in Example 5, doses were administered in 3 steps, namely, 0.05 mg, 0.1 mg and 0.2 mg. The trial drug was infused (via

31/33 intravenous) from the venous side of the dialysis circuit before the end of dialysis, three times a week, for 22 days (total of 9 times), from the first day of administration of the trial drug. Here, the test drug was administered by diluting a required dose taken from the Compound A1 bottle formulation prepared as follows with sterile water for injection and filling a syringe with the resultant according to the dose to be administered.

[00120] Each item was evaluated according to the predetermined evaluation schedule. (Compound A1 bottle formulation)

[00121] A bottle formulation that encapsulates 1 mg of Compound A1 in terms of dehydrate and sodium chloride, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate as additives in 10 ml sterile water for injection (Placebo)

[00122] A bottle formulation that encapsulates 10 ml of sterile water for injection without Compound A1 (Results) (1) Single administration: 44 cases (groups receiving Compound A1: 29 cases, placebo group: 15 cases)

[00123] Pharmacokinetic evaluation: Cmax and AUC of Compound A1 in plasma increased with increasing dose administered. t1 / 2 was 65.0-122 hours. When hemodialysis was performed 66 hours after administration, the plasma concentration of Compound A1 decreased immediately after dialysis by 75-81% than that immediately before dialysis.

[00124] Serum iPTH concentration: In the group that received Compound A1, the serum iPTH concentration became lower than immediately before administration with a single administration, where the effect continued until 66 hours after administration (immediately before gives

32/33 dialysis). Here, the variation in serum iPTH concentration 66 hours after administration was a 27% percentage decrease in the 0.025 mg dose group, 48% in the 0.05 mg dose group, 44% in the 0 dose group, 1 mg, 57% in the 0.2 mg dose group, 78% in the 0.4 mg dose group, 69% in the 0.6 mg dose group and 66% in the 0.8 mg dose group .

[00125] Safety: While vomiting and nausea were observed with a single administration in the dose groups of 0.4 mg and higher and in the dose groups of 0.6 mg and higher, respectively, both were mild and non-serious events and none another clinical problem was observed. (2) Repeated administration: 39 cases (group that received Compound A1: 28 cases, and placebo group: 11 cases)

[00126] Pharmacokinetic evaluation: Compound A1 was present mainly as an unchanged substance in plasma with repeated administration. In addition, since the minimum concentration of Compound A1 was generally constant before dialysis after the longest interval between dialysis sessions, it was found that the minimum concentration of Compound A1 in plasma did not increase before dialysis by repeated administration. Thus, it has been found that the medicinal composition of the present invention is rapidly eliminated by dialysis and does not have accumulative properties.

[00127] Serum iPTH concentration: In the group that received compound A1, the serum iPTH concentration decreased during the test period and, thus, Compound A1 maintained its effect with repeated administration. Here, the change in serum iPTH concentration on day 22 of the test (three days after the ninth administration of Compound A1) was an 8% percentage decrease in the 0.05 mg dose group, 25% in the 0 dose group , 1 mg and 36% in the 0.2 mg dose group.

[00128] Safety: Although a decrease in corrected Ca was observed in the 0.2 mg dose group and in the 0.05 mg dose group with repeated administration, all of them were mild and none caused a problem

33/33 significant to security. No decrease in corrected Ca was observed in the 0.1 mg dose group.

[00129] From the above results, it has been found that the medicinal composition of the present invention is useful as an agent to prevent or treat secondary hyperparathyroidism with reduced side effects when used in Japanese adults with a daily dose in the range of 0.025 mg to 0.8 mg.

INDUSTRIAL APPLICABILITY

[00130] The medicinal composition of the present invention is useful as an agent to prevent or treat secondary hyperparathyroidism in maintenance dialysis and the like.

Claims (14)

1. Medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis, the composition characterized by the fact that it comprises 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4- methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, in which the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults. 2. Medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis with reduced side effects, the composition characterized by the fact that it comprises 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5- chlorine-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults. 3. Medicinal composition to prevent or treat secondary hyperparathyroidism in maintenance dialysis without manifestation of significant accumulative property, the composition characterized by the fact that it comprises 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults. Medicinal composition according to any one of claims 1 to 3, characterized in that the medicinal composition is administered intravenously with a daily dose of 0.025 to 0.4 mg for adults. Medicinal composition according to any one of claims 1 to 3, characterized in that the medicinal composition is administered intravenously at the end of dialysis with a daily dose of 0.05 to 0.2 mg for adults. 6. Medicinal composition according to any one of claims 1 to 5, characterized by the fact that the end of dialysis means the end of each dialysis session in a dialysis schedule of 3 to 5 sessions per week. Medicinal composition according to any one of claims 1 to 6, characterized by the fact that 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate sodium or a solvate thereof. 8. Use of a medicinal composition, characterized by the fact that it is for the manufacture of a medicament to prevent or treat secondary hyperparathyroidism in maintenance dialysis, the composition comprising 3 - {[(2S) -2-amino-2-carboxyethyl acid ] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults. 9. Use of a medicinal composition, characterized by the fact that it is for the manufacture of a medicinal product to prevent or treat secondary hyperparathyroidism in maintenance dialysis with reduced side effects, the composition comprising 3 - {[(2S) -2-amino acid -2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg a 0.8 mg for adults. 10. Use of a medicinal composition, characterized by the fact that it is for the manufacture of a medicine to prevent or treat secondary hyperparathyroidism in maintenance dialysis without manifesting significant accumulative property, the composition comprising 3 - {[(2S) -2 -amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, where the composition is administered intravenously at the end of dialysis with a daily dose of 0.025 mg to 0.8 mg for adults. 11. Use of a medicinal composition according to any one of claims 8 to 10, characterized in that the medicinal composition is administered intravenously with a daily dose of 0.025 to 0.4 mg for adults. 12. Use of a medicinal composition according to any one of claims 8 to 10, characterized in that the medicinal composition is administered intravenously at the end of dialysis with a daily dose of 0.05 to 0.2 mg for adults . 13. Use of a medicinal composition according to any one of claims 8 to 12, characterized by the fact that the end of dialysis means the end of each dialysis session in a dialysis schedule of 3 to 5 sessions per week. 14. Use of a medicinal composition according to any one of claims 8 to 13, characterized by the fact that 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4- methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is 3 - {[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate sodium or a solvate thereof.